Production of 4-hydroxy-1,2-benzothiazine-3-carboxamides

ABSTRACT

A process for the synthesis of N-aryl-3,4-dihydro-2-alkyl-4-oxo2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides by treatment of N-aryl-N&#39;&#39;-alkyl-N&#39;&#39;-(2&#39;&#39;alkoxycarbonylbenzenesulfonyl)glycineamides, useful intermediates for said process, with an alkali or alkaline earth metal hydride in a reaction-inert solvent at 50*-150* C., said products being antiinflammatory agents.

United States Patent Lombardino PRODUCTION OF 4-HYDROXY-l ,2-BENZOTHlAZINE-3- CARBOXAMIDES Inventor: Joseph G. Lombardino, Niantic,

Conn.

Assignee: Pfizer Inc., New York, NY.

Filed: Apr. 23, 1973 Appl. No.2 353,607

US. Cl 260/243 R, 260/470, 424/246,

260/559 A, 260/561 A Int. Cl C07d 93/02 Field of Search 260/243 R References Cited UNITED STATES PATENTS 7/1971 Lombardino 260/243 [4 1 Dec. 10, 1974 Primary ExaminerJohn M. Ford Attorney, Agent, or FirmConnolly and Hutz 5 7] ABSTRACT 8 Claims, N0 Drawings PRODUCTION OF 4-HYDROXY-l ,Z-BENZOTHIAZINE-S- CARBOXAMIDES BACKGROUND OF THE INVENTION This invention relates to a process for the synthesis of 1,2-benzothiazine-3-carboxamides, and in particular to the preparation of N-aryl-3,4-dihydro-2-alkyl-4-oxo- 2I-I- l ,2-benzothiazine-3-carboxamide l,l-dioxides, a class of compounds useful as antiinflammatory agents, and to N-aryl-N'-alkyl-N-(2'-alkoxycarbonylbenzenesulfonyl)glycineamides as useful intermediates for said process.

Synthesis of 3,4-dihydro-2-alkyl-4-oxo-2H-1,2- benzothiazine-3-carboxamide l,l-dioxides has been previously achieved by amination of the corresponding 3-carboxylic acid ester or by treatment of the parent 3,4-dihydro-2-alkyl-4-oxo-2H-1 ,2-benzothiazine l,ldioxide with the appropriate isocyanate, Lombardino, et al., J. Med. Chem., 14, 1171 (1971) and Zinnes, et al., ibid., 16, 43 ([973) and U.S. Pat. No. 3,591,584. In addition, Zinnes, et al., loc. cit., has taught the preparation of 3-carboxamides by treatment of the pyrrolidine enamine of 3,4-dihydro-2-methyl-4-oxo-2I-I-l,2- benzothiazine 1,1-dioxide with phosgene followed by treatment of the resulting 3-carbonyl chloride with an appropriate amine.

US. Pat. No. 3,714,155 discloses 4-hydroxy-2,-N- dimethyl-2H-l ,2-benzothiazine-3-carboxanilide 1,1- dioxides as antiinflammatory agents, synthesized by methylation of the corresponding N-phenyl carboxamide with dimethylsulfate in the presence of sodium hydride.

SUMMARY OF THE INVENTION It has now been discovered that preparation of compounds of the formula CONHRt wherein R is selected from the group consisting of pheny; monosubstituted phenyl wherein said substituent is fluoro, chloro, methyl or methoxy; 'Z-thiazolyl; 4,5-dimethyl-2-thiazolyl; 2-pyridyl; 6-methyl-2-pyridyl; and -methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo, which comprises contacting a compound of the formula:

COzRa son lcmooNnm wherein R is alkyl containing from l to 3 carbon atoms, with an alkali or alkaline earth metal hydride in a reaction-inert solvent at 50-l50 C. leads to the desired compounds which are potent nonsteroidal antiinflammatory agents.

wherein R is selected from the group consisting of phenyl; monosubstituted phenyl wherein said substituent is fluoro, chloro, methyl or'methoxy; 2-thiazolyl; 4,5-dimethyl-2-thiazolyl; Z-pyridyl; 6-methyl-2-pyridyl; and 5-methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo.

Also considered within the scope of the instant invention is the process wherein R is alkyl of up to 8 carbon atoms, aryl or aralkyl, and wherein the metal hydride is replaced by a suitable organometallic reagent.

A preferred feature of the process leading to the compounds of the present invention is the use of sodium hydride as the metal hydride and tetrahydrofuran as the reaction-inert solvent, while the preferred intermediates are N-(aryl)-N-methyl-N-(2- alkoxycarbonylbenzenesulfonyl)glycineamides.

DETAILED DESCRIPTION OF THE INVENTION The aforementioned reaction is depicted in the following scheme wherein R R R and X are as previously described.

In the above reaction of the benzenesulfonylglycineamide with a metal hydride the ratio of reactants is two equivalents of hydride per mole of glycineamide. In practice, a slight excess of 5l0 percent over two equivalents of the metal hydride has no deleterious effeet on the formation of the desired product.

It is also desirable to conduct said reaction in a reaction-inert solvent. By such a solvent, or mixtures thereof, is contemplated those, which under the conditions of the instant process, do not enter into appreciable reaction with either the starting reagents or products. It is preferred that non-aqueous, aprotic, polar atures of 50100 C. are employed, the reaction time will vary between 4-10 hours.

Regarding temperature range, it is preferred, for practical reasons, that the instantly claimed process be heated in order to obtain optimum yields of the desired products. A temperature range of 50-150 C. is operative, with a preferred range of 50-l00 C.

At the conclusion of the cyclization reaction the mixture is cooled and added to water, to which is then added sufficient acid to render the mixture acidic to litmus paper. The product is then extracted with a waterimmiscible solvent, such as methylene chloride or chloroform, and the organic extracts concentrated to dryness. Further purification of the product is effected by recrystallization from an appropriate solvent.

The intermediate benzenesulfonylglycineamides, which are cyclized under the conditions of the present process, are prepared as shown by the following flow diagram:

SO2IIICH1 C ONHRI N-E thoxycarbonyl-2-ethoxy-1,z-dihydroquinoline The glycine derivatives (1) are readily prepared by the methods reviewed by Greenstein and Winitz, Chemistry of the Amino Acids," John Wiley & Sons, lnc., New York, New York 1961, Volumes 1-3.

As previously mentioned, the compounds ofthe present process invention are useful as antiinflammatory agents, and U.S. Pat. No. 3,591,584 teaches how to use these compounds for this utility. Of particular interest in the present invention are the synthesis of benzothiazine 1,1-dioxide wherein R is methyl, X is hydrogen and R is phenyl, Z-pyridyl, 2-thiazolyl or 6-methyl2- pyridyl.

The particularly preferred benzenesulfonylglycineamide intermediates are those wherein R is phenyl, pyridyl, Z-thiazolyl or 6-methy1-2-pyridyl and R and R are each methyl.

The examples which follow are given by way of illustration, and are not to be construed as limitations of this invention, many variations of which are possible within the scope and spirit thereof.

EXAMPLE 1 N-(Z-Thiazolyl 1-3,4-dihydro-2-methyl-4-oxo-2H-1 ,2-

benzothiazine3-carboxamide 1,1-dioxide To 25 mg. (0.068 m mole) of N-(2-thiazolyl)-N- methyl-N-(2'-methoxycarbonylbenzenesulfonyl)- glycineamide in 2 ml. of dry tetrahydrofuran maintained under a nitrogen atmosphere is added 6.5 mg. (0.135 m mole) of a 50% sodium hydride suspension in oil, and the resulting reaction mixture heated under reflux overnight. The reaction mixture comprised of a yellow suspension is quenched with ice and subse quently acidified with 3N hydrochloric acid. The prod-' uct is extracted with chloroform and the extracts combined and dried over sodium sulfate. The drying agent is filtered and the filtrate concentrated to a gum, which on trituration with 0.5 m]. of chloroform and 3 ml. of hexane yields 3.3 mg. of the desired product, m.p. l72l93 C. Recrystallization, m.p. 256 C. dec, provides material identical to that prepared in U.S. Pat. No. 3,591,584.

EXAMPLE 2 3 ,4-Dihydro-2-methyl-4-oxo-2H-1 ,Z-benzothiazine carboxanilide 1,1-dioxide To a solution of 3.77 g. (0.01 mole) of N-phenyl-N'- methyl-N'-(2-ethoxycarbonylbenzenesulfonyl)- glycineamide in 40 ml. of dimethylformamide maintained under a nitrogen atmosphere is added portionwise 960 mg. (0.02 mole) of a 50%. sodium hydride suspension in oil, and the reaction mixture heated at steam bath temperatures for 6 hrs. The mixture is cooled, poured into ice and water and acidified with 6N hydrochloric acid. The product is extracted with chloroform and the combined chloroform extracts (3) are back-washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue gum induced to crystallize by trituration with cold isopropanol. The filtered product proves to be identical with that reported in U.S. Pat. No. 3,591,584.

EXAMPLE 3 N-( 6-Methyl-2-pyridyl 3 ,4-dihydro-2 methyl-4-oxo- 2 1-1-1 ,2-benzothiazine-3-carboxamide l,l-d ioxide In a manner similar to Examples 1 and 2, 2.03 g. (S m moles) of N-(6-methyl-2-pyridyl)-N'-methyl-N'-(2'- propoxycarbonylbenzenesulfonyl)glycineamide in 25 ml. of dioxane is treated with 205 mg. (5 m moles) calcium hydride and the resulting mixture heated under reflux overnight. The cooled reaction mixture is quenched in ice, acidified, and the product extracted with methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to a gum. Trituration with cold acetonitrile followed by filtration provides the desired product.

EXAMPLE 4 3 -Chloro3 ,4-dihydro-2-rnethyl 4-oxo-2H -1 ,2 benzothiazine-3-carboxanilide 1,1-dioxide The procedure of Example 1 is repeated, starting with 4.11 g. (0.01 mole) of N-(3-chloropheny1)-N- methyl-N-(2-methoxycarbonylbenzenesulfonyl)- glycineamide and 800 mg. (0.02 mole) of a 50 percent suspension of potassium hydride in 40 ml. of dimethylsulfoxide. to yield the desired crude product. Further purification is achieved by recrystallization from acetic acid.

EXAMPLE 5 The procedure of Example 1 is again repeated, starting with the appropriate N-aryl-N-alkyl-N-(2- methoxycarbonylbenzenesulfonyl)glycineamides to provide the following congeners:

EXAMPLE 6 benzothiazine-3-carboxamide l,l-dioxide, Cal-l N-(2- furyl )-3,4-dihydro-2-methyl-4-oxo-2l-l- 1,2- benzothiazine-S-carboxamide 1,1-dioxide, Lil-l; 3'- methoxy-3,4-dihydro-2-n-propyl-4-oxo-2H-1,2- benzothiazine-3-carboxanilide 1,1-dioxide, KH: 2'- chloro-3,4-dihydro-2-ethyl-4-oxo-2H-l ,2- benzothiazine-3-carboxanilide l,l-dioxide, MgH N- (2-pyridyl)-3,4-dihydro-2-methyl-4-oxo-2l-l-l ,2- benzothiazine-3-carboxamide 1,l-dioxide, Rbl-l: N-(6- methyl-2-pyridyl)-3,4-dihydro-2-ethyl-4-oxo-2H-l ,2- benzothiazine-3-carboxamide l,l-dioxide, LiH 4'- methyl-3,4-dihydro-2-methyl-4-oxo-2H-1,2- benzothiazine-3-carboxanilide l,l-dioxide, KH; N-(2- thiazolyl)-3 ,4-dihydro-2-ipropyl-4-oxo-2H-1,2- benzothiazine-3-carboxamide l,1-dioxide, BaH N-(S- methyl-3-isoxazolyl)-3,4-dihydro-2-methyl-4-oxo-2H- l,2-benzothiazine-3-carboxamide l,l-dioxide, CaH and N-(5-methyl3-isoxazolyl)-3,4-dihydro-2-methyl- 4-oxo-2H- l ,2-benzothiazine-3-carboxamide l ,1 dioxide, Lil-l.

PREPARATION A Benzyloxycarbonylglycineamides l. N-Methyl-N '-benzyloxycarb0nyl-N-( 2- thiazolyl)glycineamide To a yellow solution of 9.44 g. (42.3 m moles) of commercially available N-benzyloxycarbonyl-N- methylglycine and 4.8 g. (48 m moles) of 2- aminothiazole in ml. of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise l3 g. (53 m moles) of N-ethoxycarbonyl-Z-ethoxy-l ,2- dihydroquinoline in 75 ml. of the same solvent. The resulting reaction mixture is allowed to stir at room temperature for l hr. and is then heated under reflux for 2 hrs. The solution is cooled in ice and the resulting solids filtered and dried, 4.6 g., m.p. 203205 C.

Anal. Calcd for C l-I O N S: C, 55.06; H, 4.59; N, 13.76.

Found; C, 55.02; H, 4.94; N, 13.7l. 2. In a similar manner to Preparation A-l, starting with the requisite glycine derivative and aryl amine, the following benzyloxycarbonylglycineamides are synthesized as intermediates:

1' 2 Q) CHZO CO NCHnCONHRl PREPARATION B Glycineamides l. N '-Methyl-N-(2-thiazolyl )glycineamide (3: R CH;,; R 2C H NS) To 5 g. of N'-methyl-N-benzyloxycarbonyl-N-(2- thiazolyl)glycineamide under a nitrogen atmosphere is added slowly with stirring 50 ml. of a 33 percent hydrogen bromide solution in acetic acid. After the vigorous evolution of carbon dioxide has subsided, the reaction mixture is allowed to stir at room temperature overnight. Diethyl ether (275 ml.) is added and the precipi tated solids filtered and dried, 5.4 g., m.p. 242-244 C., dec.

The analytical sample is recrystallized from ethanoldiethyl ether.

Anal. Calc'd for C H ON S.2HBr: C, 21.64; H, 3.33, N, 12.62.

Found: C, 22,36; H, 3.34; N, 12.87.

The free base is generated by treatment of an aqueous solution of the hydrobromide salt with an aqueous sodium hydroxide solution, followed by extraction of the free base into a water-immiscible solvent such as benzene.

2. N-Alkyl-N-Arylglycineamides Starting with the requisite intermediate from Preparation A-2 and following the procedure of Preparation B-l the following intermediate products are prepared:

PR EPARATlON C Z-Carboalkoxybenzenesulfonyl Chlorides 1. A heavy precipitate resulting from the addition of 85 ml. of l2N hydrochloric acid to 37.8 g. of methyl anthranilate in 50 ml. of cold water is stirred and maintained at 0-5 C. in an ice bath while 19.0 g. of sodium nitrite in ml. of cold water is added dropwise. The resulting pale yellow soltuion is stirred for 30 min. at 0-5 C. and is filtered through a sentered glass filter.

The above filtrate containing the diazonium salt is slowly added dropwise to a solution resulting from the addition of a cold solution of g. of sulfur dioxide in 200 ml. of glacial acetic acid to a cold suspension of 8 65 g. of cupric chloride in 11 1 ml. of glacial acetic acid.

During the second half of the addition and for 20 min. after the addition is complete. gas evolution is evident.

After stirring the reaction mixture for 1 hr. in the cold, 1.4 l. of ice water is added and the precipitate interme diate product is filtered and dried in vacuo, 9.2 g., m.p. 62 C.

Meerwein, et al., Chem. Ber, 90. 841 (1957) reports a mp of 6465 C. for this compound which is prepared by a similar procedure. 2. Substituted 2-Carboalkoxybenzenesulfonyl chlorides Starting with the appropriately substituted anthranilic acid esters which are either known in the chemical literature or readily prepared by methods known to those skilled in the art and employing the procedure of Meerwein, et a1. or that of Preparation C- l, the follow ing sulfonyl chlorides are synthesized:

PREPARATION D N-Benzenesulfonylglycineamides 1. N-(2-Thiazolyl)-N'-methyl-N-(2' methoxycarbonylbenzenesulfonyl)glycineamide N-Methyl-N-(Z-thiazolyl)glycinemide, generated from 4.84 g. of the corresponding dihydrobromide salt, in 50 ml. of benzene is treated with 3.41 g. of 2- methoxycarbonylbenzenesulfonyl chloride, and the resulting mixture heated under reflux for 30 hrs. The reaction mixture is cooled and the precipitated solids filtered, washed with benzene and partitioned between water and chloroform. The water layer is extracted several additional times with chloroform, and the chloroform extracts combined and dried over sodium sulfate. The organic solvent is removed in vacuo and the tan residual solid is triturated with hexane and filtered, 640 mg, mp 215 C. dec. The analytical sample is recrystallized from methanol, mp. 216-2l8 C. dec.

Anal. Calcd for C H O N S C, 45.52; H, 4.09; N, 1 1.37.

Found: C, 45.02; H, 4.12; N, 11.71. 2. N-Aryl-N'-alkyl-(2-alkoxycarbonylbenzenesulfonyl)glycineamides Starting with the requisite intermediates from Preparations B and C and employing the procedure of Preparation D-l, the following intermediates are prepared:

ii it:

p 10 PREPARATION E Metal Hydrides The metal hydrides utilized in the present'process are either commercially available or are prepared by literature procedures, Moeller, Inorganic Chemistry," John Wiley Sons, New York, New York 1959.

What is claimed is: i

l. A process for the preparation of a compound of the formula:

X is a substituent selectedfrom the group consisting of hydrogen, methyl, methoxy, fluoro, chlo ro and bromo, which comprises contacting a compound of the formula:

S021TICH:CONHR1 R2 wherein R is alkyl containing from 1 to 3 carbon atoms, with a metal hydride selected from the group consisting of alkali and alkaline earth metal hydrides, in a reaction-inert solvent at 50-l50 C 2. The process of claim 1 wherein the metal hydride is sodium hydride. l

3. The process of claim 2 wherein the solvent is tetrahydrofuran.

4. The process of claim 3 wherein X is hydrogen, and R and R, are each methyl. q

5. The process of claim 4 wherein R, is phenyl.

6. The process of claim 4 wherein R, is 2-thiazolyl.

7. The process of claim 4 wherein R, is 6-methyl-2- pyridyl. I

8. The process of claim 4 wherein R, is Z-pyridyl. 

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA:
 2. The process of claim 1 wherein the metal hydride is sodium hydride.
 3. The process of claim 2 wherein the solvent is tetrahydrofuran.
 4. The process of claim 3 wherein X is hydrogen, and R2 and R3 are each methyl.
 5. The process of claim 4 wherein R1 is phenyl.
 6. The process of claim 4 wherein R1 is 2-thiazolyl.
 7. The process of claim 4 wherein R1 is 6-methyl-2-pyridyl.
 8. The process of claim 4 wherein R1 is 2-pyridyl. 